In a highly anticipated decision announced this week, the US Food and Drug Administration (FDA) approved the use of Revlimid® in the frontline setting based upon the results of the FIRST trial (which I have discussed in the IMF’s presentation on news from the 2014 American Society of Hematology meeting here). Ongoing Revlimid/dexamethasone was clearly superior to a previous standard of care, Melphalan/Prednisone/Thalidomide (MPT), as well as shorter-duration use of Revlimid/Dexamethasone (Rd).
This approval consolidates what has been widespread off-label use of Revlimid in the frontline setting in the US for several years. Practitioners and patients in the US are very fortunate that the off-label mechanism has allowed flexible use of Revlimid, including its use in the popular Velcade®/Revlimid/dexamethasone combination for induction therapy.
The FDA has also added much more detailed guidance than in the past, recommending stem-cell harvesting after the first four cycles of therapy, if possible, and much closer blood-count monitoring. There is also a particular caution about the potential risk of second primary malignancies (SPMs) in the post-transplant Revlimid maintenance setting. With these caveats it is important to note that ongoing use of Revlimid (so-called continuous therapy) is supported by this decision.
The likely approval of frontline Revlimid in Europe in the coming weeks is much more significant for European patients and physicians. Right now, frontline use is not possible. The pending approval will allow use specifically of Revlimid plus low-dose (weekly) dexamethasone exactly as used in the FIRST trial. This is a key point—the triple combination of VRd will not be immediately approved. Use is restricted to the FIRST trial protocol schedule only. This restriction is becoming an increasingly troubling problem because of the difficulty of completing multiple trials to encompass all the potential treatment combinations. Regulators use the lack of data to restrict the expense of broader use. This is an artificial constraint in that the efficacy and safety of many other combinations is widely known and well documented in the medical literature.
Implications of drug approvals in 2015 and beyond
What is frequently not so clear is the exact comparative efficacy and safety of different combination regimens. For example, how does VRD (Velcade/Rev/DEX ) compare to VCD (the CyBorD regimen) as a primary induction treatment?  Without a direct head-to-head comparison, one can say that the percentage and depth of responses and overall outcomes are rather similar. Both three-drug regimens are also safe, well tolerated, and more active than the two-drug combinations of Rev/dex (just approved) or Velcade/dex, also previously approved. Regulators, however, can point to the substantial cost savings of using VCD versus VRD, as well as the benefit of saving Revlimid for use in an approved relapse setting after VCD.  How best to combine and sequence drugs is a legitimate question without an immediate, clear answer, for sure!
In the US,  selecting among available therapy options falls into the realm of the treating physician working within NCCN guidelines and currently allowed off-label use, neither of which requires validation based on clinical trials of direct comparators. In Europe and elsewhere around the globe, the American scenario  cannot occur. Regulators require trial comparisons.
Thinking about the number (and potential cost) of trials needed to resolve all these questions is mind-numbing! In the interim, cost and regulatory control become the final arbiters limiting new drug use to the exact trial schedule(s) – IF the cost can be justified using trial endpoints and quality-of-life indicators.
Layered on top of comparative drug efficacy are safety concerns in particular circumstances. In the FIRST trial, ongoing Revlimid use as a frontline approach is both safe and very efficacious. But does this mean that similar ongoing use of Revlimid as post-transplant maintenance can be viewed equally? Lingering concerns remain about how best to use Revlimid as post-transplant maintenance. Is Revlimid maintenance recommended for many patients, but not all? Should maintenance be indefinite or for a defined period to maximize benefit? Revlimid used along with oral melphalan or as consolidation and maintenance immediately after high-dose intravenous melphalan, as in the IFM trial, may carry an extra risk of SPMs, including otherwise unexpected lymphoid malignancies such as ALL. It is thus difficult to give blanket approval for the use of any drug in all circumstances—no matter how efficacious and safe overall. 
Should treatment decisions fall within the realm of the primary physician, as they do here in the US? Or should options be left to the discretion of regulators, as is the case elsewhere in the world?
There is much to celebrate as Revlimid is fully available in the frontline setting, but many issues that will limit ideal global access and use remain to be resolved.
Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to InfoLine hours are 9 am to 4 pm PT. Thank you.